2-phenyl-imidazopyridin-ones and also useful as cardiotonics and anti-hypertensives

ABSTRACT

Compounds of the formula ##STR1## wherein A, B, C and D are --N═, HN═, R 3  N═, O═C═, HC.tbd., HO--C.tbd. or R 3  SO 2  --O--C.tbd.; and 
     R 1  and R 2  are substituents of various types. 
     The compounds are useful as hypotensives and cardiotonics.

This is a division of copending application Ser. No. 623,718, filed June22, 1984, now U.S. Pat. No. 4,670,438.

This invention relates to novel 2-phenyl-imidazoles and acid additionsalts thereof, to methods of preparing these compounds, topharmaceutical compositions containing them as active ingredients, andto a method of using them an antihypertensives and cardiotonics.

THE PRIOR ART

Imidazo[4,5-c]pyridines having useful pharmacological properties aredisclosed in European applications No. 0,072,926 and No. 0,079,083.

THE INVENTION

More particularly, the present invention relates to a novel class ofcompounds represented by the formula ##STR2## wherein A, B, C and D areeach independently ##STR3## provided, however, that at least one of A,B, C and D must be HN═ and another must be O═C═; or at least one of A,B, C and D must be --N═ and another must be ##STR4## or one of A, B, Cand D may also be a chlormethine group if at least two of A, B, C and Dare --N═;

R₁ is NC--CH₂ --O--, HOOC--CH₂ --O--; R₃ --OOC--CH₂ --O--, R₃ SO₂ --O--,R₃ SO₂ --NH--, R₃ SO₂ --NR₃ --, R₄ --O--, or, when A, B, C and Dtogether with the condensed imidazole ring is other thanimidazo[4,5-c]pyridine, also hydroxyl;

R₂ is R₃ O--, ##STR5## or R₅ --O--; R₃ is alkyl of 1 to 4 carbon atoms;

R₄ is alkynyl of 2 to 5 carbon atoms or, when A, B, C and D togetherwith the condensed imidazole ring is other than imidazo[4,5-c]pyridine,also alkenyl of 2 to 5 carbon atoms; and

R₅ is alkenyl of 2 to 5 carbon atoms or alkinyl of 2 to 5 carbon atoms;

tautomers thereof; and non-toxic, pharmacologically acceptable acidaddition salts thereof.

The present invention thus relates to novelimidazo[4,5-b]pyridin-5-ones, imidazo[4,5-b]pyridin-7-ones,6-hydroxy-imidazo[4,5-b]pyridines, imidazo[4,5-c]pyridin-6-ones,imidazo[4,5-c]pyridin-4-ones, 7-hydroxy-imidazo[4,5-c]pyridines,imidazo[4,5-c]pyridazin-3-ones, imidazo[4,5-d]pyridazin-4-ones,imidazo[4,5-b]pyrazin-5-ones, purin-2-ones, purin-6-ones,purin-2,6-diones, imidazo[4,5-e]triazin-6-ones,imidazo[4,5-d]triazin-7-ones alkanesulfonyloxy-imidazo[4,5-b]pyridines,alkanesulfonyloxy-imidazo[4,5-c]pyridines, alkanesulfonyloxy-purines,alkanesulfonyloxy-imidazo[4,5-c]pyridazines,alkanesulfonyloxyimidazo[4,5-d]pyridazines,alkanesulfonyloxy-imidazo[4,5-b]pyrazines,alkoxy-imidazo[4,5-b]pyridines, alkoxy-imidazo[4,5-c] pyridines,alkoxypurines, alkoxy-imidazo[4,5-c]pyridazines,alkoxy-imidazo[4,5-b]pyrazines, chloro-purines,chloro-imidazo[4,5-c]pyridazines, chloro-imidazo[4,5-d]pyridazines andchloroimidazo[4,5-b]pyrazines of the formula I above, tautomers and acidaddition salts thereof, particularly non-toxic, pharmacologicallyacceptable acid addition salts thereof formed with inorganic or organicacids, processes for preparing these compounds, and pharmaceuticalcompositions containing them.

Examples of specific embodiments of radicals R₁, R₂ and R₃ thefollowing:

R₁ : cyanomethoxy, hydroxycarbonylmethoxy, methoxycarbonylmethoxy,ethoxycarbonylmethoxy, propoxycarbonylmethoxy,isopropoxycarbonylmethoxy, methanesulfonyloxy, ethanesulfonyloxy,propanesulfonyloxy, isopropanesulfonyloxy, n-butanesulfonyloxy,methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino,N-methyl-methanesulfonylamino, N-isopropyl-methanesulfonylamino,N-ethyl-ethanesulfonylamino, N-n-propyl-ethanesulfonylamino,N-methyl-propanesulfonylamino, N-ethyl-propanesulfonylamino, vinyloxy,allyloxy, crotyloxy, pent-2-enyloxy, pent-3-enyloxy or propargyloxy;

R₂ : methoxy, ethoxy, propoxy, isopropoxy, dimethylamino, diethylamino,dipropylamino, diisopropylamino, ethyl-methylamino, ethyl-propylamino,vinyloxy, allyloxy, crotyloxy, pent-2-enyloxy, pent-3-enyloxy orpropargyloxy;

R₃ : methyl, ethyl, n-propyl, isopropyl or n-butyl.

A preferred subgenus is constituted by those compounds of the formula Iwhere

A, B, C, D, R₁ and R₂ have the meanings previously defined,

R₃ is methyl, and

R₄ and R₅ are each independently allyl or propargyl,

especially those where R₁ is in the 4-position and R₂ is in the2-position of the phenyl ring, and acid addition salts thereof,particularly non-toxic, pharmacologically acceptable acid addition saltsthereof.

A particularly preferred subgenus is constituted byimidazo[4,5-b]pyridin-5-ones, imidazo[4,5-c]pyridin-4-ones,imidazo[4,5-c]pyridin-6-ones, imidazo[4,5-c]pyridazin-3-ones,imidazo[4,5-d]pyridazin-4-ones, imidazo[4,5-b]pyrazin-5-ones,purin-2-ones, purin-6-ones, purine-2,6-diones andimidazo-[4,5-e]triazin-6-ones of the formula I, where

R₁ is propargyloxy, methanesulfonyloxy, methanesulfonylamino orN-methyl-methanesulfonylamino or, when A, B, C and D together with thecondensed imidazole ring is other than imidazo[4,5-c]pyridine, alsoallyloxy; and

R₂ is methoxy or dimethylamino,

especially those where R₁ is in the 4-position and R₂ is in the2-position of the phenyl ring, and acid addition salts thereof,particularly non-toxic, pharmacologically acceptable acid addition saltsthereof.

The compounds embraced by formula I may be prepared by the followingmethods:

Method A

By cyclizing a compound of the formula ##STR6## wherein A', B', C' andD' have the meanings previously defined for A, B, C and D or one of themis an oxymethine group protected by a protective group,

one of X and Y is hydrogen and the other or both X and Y are ##STR7##where R₂ has the meanings previously defined,

R₁ ' has the meanings previously defined for R, or is hydroxyl protectedby a protective group;

Z₁ and Z₂ are each individually amino, substituted amino, hydroxyl,lower alkoxy, mercapto or lower alkylthio, or

Z₁ and Z₂ together are oxygen, sulfur, imino, (alkyl of 1 to 3 carbonatoms)imino, (alkylene of 2 to 3 carbon atoms)dioxy or (alkylene of 2 to3 carbon atoms)dithio;

and, if desired, subsequently splitting off residual protective groups.

The protective groups may be conventional protective groups forhydroxyl, that is, acyl such as acetyl, propionyl or benzoyl, or benzyl.

The cyclization is advantageously carried out in a solvent such aswater, ethanol, isopropanol, glacial acetic acid, benzene,chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether,diethyleneglycol dimethyl ether, sulfolane, dimethylformamide, tetralinor a mixture of any two of these, or in an excess of the acylating agentused to prepare the compound of the formula II, for instance in thecorresponding nitrile, anhydride, acid halide, ester, amide ormethiodide, for example at temperatures between 0° and 250° C., butpreferably at the boiling point of the reaction mixture, optionally inthe presence of a condensation agent such as phosphorus oxychloride,thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonicacid, hydrochloric acid, phosphoric acid, polyphosphoric acid, aceticacid anhydride or possibly also in the presence of a base such as sodiumhydroxide, potassium ethoxide or potassium tert. butoxide. However, thecyclization may also be carried out without a solvent and/or condensingagent.

Any protective group used in the reaction is subsequently split off byhydrolysis or hydrogenation. However, if an acyl group is used as theprotective group, the protective group may be split off during thereaction.

The removal of a protective group by hydrolysis is advantageouslycarried out in an aqueous or alcoholic solvent such as water,water/methanol, water/dioxane or methanol in the presence of an acidsuch as hydrochloric acid or a base such as sodium hydroxide solution orammonia at temperatures up to the boiling point of the solvent which isused.

The removal of a protective group by hydrogenation is carried out in asolvent such as ethyl acetate, glacial acetic acid or methanol, withhydrogen in the presence of a hydrogenation catalyst such as platinum orpalladium-on-charcoal, optionally in the presence of a base such assodium hydroxide or potassium hydroxide.

Method B

By rearrangement of an N-oxide of the formula ##STR8## wherein A, B, C,D, R₁ and R₂ have the meanings previously defined, optionally followedby hydrolysis.

The reaction is advantageously carried out in a solvent such as benzene,in the presence of an acylating agent such as acetic acid anhydride orpropionic acid anhydride which may also be used as the solvent, atelevated temperatures, but preferably at the boiling point of thesolvent which is used.

The subsequent hydrolysis is advantageously carried out in water,water/methanol, water, dioxane or methanol, in the presence of an acidsuch as hydrochloric acid or a base such as sodium hydroxide or ammonia,at the boiling point of the reaction mixture.

Method C

For the preparation of a compound of the formula I wherein R₁ isalkanesulfonyloxy, alkanesulfonylamino or N-alkyl-alkanesulfonylaminoand/or one of A, B, C and D is ##STR9##

By reacting a compound of the formula ##STR10## wherein R₂ has themeanings previously defined, and

A", B", C", D" and R₁ " have the meanings previously defined for A, B,C, D and R₁, respectively, but either R₁ " must be hydroxyl, amino oralkylamino or one of A", B", C" and D" must be HO--C.tbd.,

with a sulfonyl halide of the formula

    Hal--SO.sub.2 R.sub.3                                      (V)

wherein R₃ has the meanings previously defined, and Hal is chlorine orbromine, followed by partial hydrolysis, if desired.

The reaction is carried out in a solvent such as water, tetrahydrofuran,dioxane or dimethylformamide, in the presence of an acid-binding agentsuch as sodium hydroxide, sodium hydride, potassium tert.butoxide,triethylamine, ethyl-diisopropylamine or pyridine, where the last threemay also be used as solvents, at temperatures between 0° and 100° C.,preferably at temperatures between 20° and 50° C.

For the preparation of a compound of the formula I wherein R₁ isalkanesulfonyloxy, it is advantageous to proceed via partial hydrolysisof the reaction product thus obtained.

The optional subsequent hydrolysis is advantageously carried out inwater, water/methanol, water/dioxane or in an alcohol such as methanol,ethanol or isopropanol, in the presence of an acid such as hydrochloricacid, optionally by heating to the boiling point of the solvent which isused.

Method D

For the preparation of a compound of the formula I wherein R₁ or R₁ andR₂ is alkenyloxy or alkynyloxy or R₂ is alkoxy:

By reacting a compound of the formula ##STR11## wherein A, B, C and Dhave the meanings previously defined, and

R₁ "' R₂ ' have the meanings previously defined for R₁ and R₂,respectively, but at least one of R₁ "' and R₂ ' must be hydroxyl,

with a halide of the formula

    Hal--R.sub.6                                               (VII)

wherein

R₆ has the meanings previously defined for R₃, R₄ and R₅, and

Hal is chlorine, bromine or iodine.

The reaction is advantageously carried out in a solvent such astetrahydrofuran, dioxane, dimethylformamide, sulfolane,dimethylsulfoxide or ethyleneglycol dimethyl ether, preferably in thepresence of an acid binding agent such as potassium carbonate, potassiumtert.butoxide or sodium hydride, at temperatures between 0° and 100° C.,but preferably at temperatures between 20° and 50° C.

The compounds embraced by formula I are basic and therefore formaddition salts with inorganic or organic acids. Examples of non-toxic,pharmacologically acceptable acid addition salts are those formed withhydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, succinic,tartaric, citric, lactic, maleic or methanesulfonic acid.

The starting compounds of the formulas II to VII are either known fromthe literature or may be obtained by methods described in theliterature. For example, the starting compounds of the formula II may beobtained by acylation of the corresponding o-diamino compounds or byreduction of the corresponding acylamino-nitro compounds, while thecompounds of the formula IV or VI may be obtained by subsequentcyclization, and the compounds of the formula III are obtained byadditional N-oxidation (see British Pat. No. 810,545 and EuropeanApplication No. 024,290).

The following examples illustrate the present invention and will enableothers skilled in the art to understand it more completely. It should beunderstood, however, that the invention is not limited solely to theparticular examples given below.

EXAMPLE 12-(2-Methoxy-4-methanesulfonyloxy-phenyl)-4H-imidazo[4,5-b]pyridin-5-one(a)2-(2-Methoxy-4-methanesulfonyloxy-phenyl)imidazo[4,5-b]pyridin-4-oxide

3.19 g of2-(2-methoxy-4-methanesulfonyloxy-phenyl)imidazo[4,5-b]pyridine weredissolved in 25 ml of and then 5 ml of 30% hydrogen peroxide were addeddropwise thereto. The mixture was refluxed for one hour and concentratedto about one-tenth of its volume. The residue was poured onto ice anddigested until it had crystallized throughout. Yield: 2.1 g (63% oftheory). Melting point: 110°-125° C.

(b)2-(2-Methoxy-4-methanesulfonyloxy-phenyl)-4H-imidazo[4,5-b]pyridin-5-one

2 g of the product obtained in (a) were dissolved in 20 ml of aceticacid anhydride, and the solution was refluxed for 2.5 hours. Thereafter,the solution was concentrated by evaporation in vacuo, the residue wasmixed with 10 ml of 2N hydrochloric acid, and the mixture was boiled for20 minutes while stirring. After it had cooled, the reaction product wasprecipitated by the addition of sodium acetate and purified bychromatography on silica gel (eluant: methylene chloride/ethanol 1:0 to1:0.1). Yield: 0.72 g (36% of theory). Melting point: 258°-259° C.(decomp.).

The following compounds were obtained analogously:

2-(2-Methoxy-4-propanesulfonyloxy-phenyl)-4H-imidazo[4,5-b]pyridin-5-one,

Melting point: 193°-195° C.

2-(2-Methoxy-4-ethanesulfonyloxy-phenyl)-4H-imidazo[4,5-b]pyridin-5-one,Melting point: 241°-244° C.

2-(2-Methoxy-4-isopropylsulfonyloxy-phenyl)-4H-imidazo[4,5-b]pyridin-5-one,Melting point: 258°-261° C.

2-(2-Methoxy-4-n-butylsulfonyloxy-phenyl)-4H-imidazo[4,5-b]pyridin-5-one,Melting point: 203°-205° C.

EXAMPLE 22-(2-Methoxy-4-methanesulfonylamino-phenyl)-4H-imidazo[4,5-b]pyridin-5-one

2.7 g of5-amino-6-(2-methoxy-4-methanesulfonylaminobenzoyl-amino)-2-pyridonewere refluxed in 50 acetic acid for 1.5 hours. The mixture was thenconcentrated by evaporation in vacuo, and the residue was purified onsilica gel (eluant: methylene chloride/ethanol 1:0 to 1:0.1). Yield: 0.1g (4% of theory). Melting point: above 255° C.

Calculated: C-50.29%; H-4.22%; N-16.76%; S-9.54%. Found: C-49.95%;H-4.48%; N-16.52%; S-9.49%.

The following compounds were obtained analogously:

2-(2-methoxy-4-methanesulfonylamino-phenyl)-4H-imidazo[4,5-d]pyridazin-4-one,Melting point: 310°-314° C. (decomp.).

8-(2-methoxy-4-methanesulfonyloxy-phenyl)-1H,3H-purin-2,6-dione, Meltingpoint: 305°-307° C. (decomp.).

8-(2-methoxy-4-methanesulfonylamino-phenyl)-3(1)H-purin-2-one, Meltingpoint: 230°-232° C.

8-(2-methoxy-4-cyanomethoxy-phenyl)-3(1)H-purin-2-one,

8-(2-methoxy-4-propargyloxy-phenyl)-3(1)H-purin-2-one, Melting point:above 300° C.

Calculated: C-60.80%; H-4.08%; N-18.91%. Found: C-60.96%; H-4.09%;N-18.32%.

2-(2-methoxy-4-cyanomethyloxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one,

2-(2-methoxy-4-ethoxycarbonylmethyloxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one,

2-(2-methoxy-4-carboxymethyloxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one,

2-(2-methoxy-4-allyloxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one,

8-[2-dimethylamino-4-(N-methyl-N-methanesulfonylamino)phenyl]-3(1)H-purin-2-one,

2-(2-dimethylamino-4-methanesulfonylamino-phenyl)-4H-imidazo[4,5-b]pyridin-5-one.

EXAMPLE 3 8-(2-Methoxy-4-methanesulfonyloxy-phenyl)-3(1)H-purine-2-one

1 g of 8-(2-methoxy-4-hydroxyphenyl)-3(1)H-purin-2-one was suspended in10 ml of pyridine. 2 ml of methanesulfonyl chloride were added dropwisewhile stirring. The mixture was stirred for 15 minutes more, then 3 mlof water were added, and the mixture was concentrated by evaporation invacuo. The residue was combined with water, and the solid product whichprecipitated was purified on silica gel (eluant: methanol). Yield: 0.11g (8.5% of theory). Melting point: 233°-235° C. (decomp.).

The following compounds were obtained analogously:

2-(2-methoxy-4-methanesulfonyloxy-phenyl)-4H-imidazo[4,5-d]pyridazin-4-one(in the work-up step, hydrochloric acid was added and the mixture wasdigested), Melting point: 294°-296° C. (decomp.).

2-(2-methoxy-4-methanesulfonyloxy-phenyl)-5(7)H-imidazo[4,5-e]triazin-6-one

2-(2-methoxy-4-methanesulfonyloxy-phenyl)-4H-imidazo[4,5-c]pyridin-6-one(in the work-up step, hydrochloric acid was added),

8-(2-dimethylamino-4-methanesulfonyloxy-phenyl)-(1)H-purin-2-one,

2-(2-dimethylamino-4-methanesulfonyloxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one,

8-(2-dimethylamino-4-methanesulfonylamino-phenyl)-1H,3H-purin-2,6-dione,

6-methoxy-2-(2-methoxy-4-methanesulfonyloxy-phenyl)imidazo[4,5-c]pyridine,Melting point: 231° C. (decomp.).

2-(2-methoxy-4-methanesulfonylamino-phenyl)-4H-imidazo[4,5-d]pyridazin-4-one,Melting point: 310°-314° C. (decomp.).

6-(2-methoxy-4-methanesulfonyloxy-phenyl)-5H-imidazo[4,5-c]pyridazin-3-one,

6-(2-methoxy-4-methanesulfonylamino-phenyl)-5H-imidazo[4,5-c]pyridazin-3-one,Melting point: 320°-322° C. (decomp.)

2-methoxy-8-(2-ethoxy-4-methanesulfonyloxy-phenyl)-purin, Melting point:127°-130° C.

2-methoxy-8-(2-propoxy-4-methanesulfonyloxy-phenyl)purin, Melting point:173°-175° C.

8-(2-ethoxy-4-methanesulfonyloxy-phenyl)-3(1H)-purin-2-one,

8-(2-propoxy-4-methanesulfonyloxy-phenyl)-3(1H)-purin-2-one.

EXAMPLE 42-(2-Methoxy-4-methanesulfonyloxy-phenyl)-4-methanesulfonyloxy-imidazo[4,5-c]pyridine

1 g of 2-(2-methoxy-4-hydroxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one wassuspended in 10 ml of pyridine. After the addition of 2 ml ofmethanesulfonyl chloride, the mixture was stirred for 2 hours more atroom temperature. The reaction mixture was mixed with water, and thereaction product was thus precipitated. Yield: 1.08 g (77% of theory).Melting point: decomposition from 164° C.

Calculated: C-43.58%; H-3.66%; N-10.16%; S-15.51%. Found C-43.30%;H-3.75%; N-10.05%; S-15.73%.

The following compound was obtained analogously:

2-(2-methoxy-4-methanesulfonyloxy-phenyl)-6-methanesulfonyloxy-imidazo[4,5-b]pyridine,Melting point: 188°-189° C.

EXAMPLE 52-(2-Methoxy-4-methanesulfonyloxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-onehydrochloride

0.65 g of2-(2-methoxy-4-methanesulfonyloxy-phenyl)-4-methanesulfonyloxy-imidazo[4,5-c]pyridine was dissolved in 35 ml of ethanolic hydrochloric acid,and the solution was stirred for an hour at room temperature. Theprecipitate which had formed was suction-filtered off and washed withethanol. Yield: 0.53 g (91% of theory). Melting point: 193°-195° C.(decomp.).

EXAMPLE 62-(2-Methoxy-4-propargyloxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one

1 g of 2-(2-methoxy-4-hydroxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one wassuspended in 30 1.41 g of potassium carbonate were added, and themixture was stirred at room temperature. After 15 minutes and againafter one hour, 0.9 ml of propargyl bromide was added, and the mixturewas then stirred for another 1.25 hours. The solvent was substantiallyevaporated in vacuo, and the residue was stirred with methylenechloride. After the precipitate had been filtered off and washed withwater, the product contained in the organic phase was purified on asilica gel column (eluant: methylene chloride/ethanol 1:0 to 1:0.03).The product crystallized with half a mol of ethanol. Yield: 0.07 g (7%of theory). Melting point: 178°-180° C.

EXAMPLE 72-(2-Methoxy-4-methanesulfonyloxy-phenyl)-4H-imidazo[4,5-b]pyrazin-5-one

This compound was prepared analogous to Example 1(b) from 0.75 g of2-(2-methoxy-4-methanesulfonyloxy-phenyl) imidazo[4,5-b]pyrazin-4-oxide(heated for 1.5 hours with acetic acid anhydride). Yield: 0.13 g (17% oftheory). Melting point: above 260° C.

Calculated: C-46.44%; H-3.60%; N-16.66%; S-9.55%. Found: C-46.34%;H-3.86%; N-16.50%; S-9.29%.

EXAMPLE 82-(2-Methoxy-4-methanesulfonyloxy-phenyl)-5-methanesulfonyloxy-imidazo[4,5-b]pyridineand 2-(2-Methoxy-4-hydroxy-phenyl)-5-methanesulfonyloxyimidazo[4,5-b]pyridine

1.6 g of 2-(2-methoxy-4-hydroxy-phenyl)-4H-imidazo-[4,5-b]pyridin-5-onewere dissolved in 25 ml of pyridine, the solution was mixed with 0.6 mlof methanesulfonyl chloride, and the mixture was stirred overnight atroom temperature. 50 ml of ice were added, and the mixture was made acidwith 20 ml of concentrated hydrochloric acid. It was then heated for 1.5hours on a steam bath, then cooled, and the product which precipitatedwas purified by chromatography on silica gel (eluant: methylenechloride/ethanol 1:0.01 to 1:0.2).

Fraction I:

Yield: 0.18 g (10% of theory) of 2-(2-methoxy-4-methanesulfonyloxy-phenyl)-5-methanesulfonyloxy-imidazo[4,5-b]pyridine, Meltingpoint: 223°-225° C.

Fraction II:

Yield: 0.21 g (15% of theory) of2-(2-methoxy-4-hydroxyphenyl)-5-methanesulfonyloxy-imidazo[4,5-b]pyridine,Melting point: 227°-228° C.

EXAMPLE 9 2-(2-Methoxy-4-hydroxy-phenyl)-4H-imidazo[4,5-b]pyridin-5-one

3.95 g of 5-nitro-6-(2-methoxy-4-benzyloxy-benzoylamino)-2-pyridone werehydrogenated in 350 ml of glacial acetic acid after the addition of 1 gof 10% palladium-on-charcoal for 1.7 hours at 80° C. under a pressure of5 bar. The reaction mixture was then stirred at 100° C. for 1.3 hours.The catalyst was filtered off, and the filtrate was allowed to cool. Theproduct which precipitated was washed with ether. By evaporating thefiltrate and adding ether, further fractions were obtained. Yield: 2.3 g(60% of theory). Melting point: over 270° C.

Calculated: C-54.10%; H-5.07%; N-11.13%. Found: C-54.38%; H-4.96%;N-11.04%.

EXAMPLE b 102-(2-Methoxy-4-methanesulfonylamino-phenyl)-6-hydroxy-imidazo[4,5-b]pyridine

0.5 g of 2,3-diamino-5-acetoxy-pyridine and 0.83 g of2-methoxy-4-methanesulfonylamino-benzoic acid were refluxed for one hourin 20 ml of phosphorus oxychloride. The reaction mixture was combinedwith ice water and then ad]usted to pH 7 with concentrated aqueousammonia. The product was then extracted with ethyl acetate and purifiedby column chromatography (silica gel, eluant: methylene chloride/ethanol1:0.02 to 1:0.1). Yield: 0.06 g (6% of theory). Melting point: 225° C.(decomp.).

The following compound was obtained analogously:

2-methoxy-8-(2-methoxy-4-propargyloxy-phenyl)purine. Melting point:148°-150° C.

EXAMPLE 11 2-Chloro-8-(2-methoxy-4-propargyloxy-phenyl)purine

2.5 g of2-chloro-8-(2-methoxy-4-propargyloxy-benzoylamino)-5-amino-pyrimidinewere dissolved in a mixture of 50 ml of 2N sodium hydroxide and 50 ml ofethanol, and the solution was refluxed for 2 hours. The mixture wasdiluted with 50 ml of ice water, and a precipitate was obtained byacidifying with glacial acetic acid. The precipitate wassuction-filtered off, taken up in acetone/methylene chloride, and thesolution was dried over magnesium sulfate and evaporated to dryness invacuo. The residue was triturated with ether and suctionfiltered. Yield:1.4 g (64% of theory). Melting point: 229°-231° C. (decomp.).

EXAMPLE 12 8-(2-Methoxy-4-methanesulfonyloxy-phenyl)-purin-6-one (a)6-Methanesulfonyloxy-8-(2-methoxy-4-methanesulfonyloxy-phenyl)purine

This compound was prepared analogous to Example 4. The product was usedin the next step without any further purification.

(b) 8-(2-Methoxy-4-methanesulfonyloxy-phenyl)purin-6-one

This compound was prepared analogous to Example 5 from6-methanesulfonyloxy-8-(2-methoxy-4-methanesulfonyloxy-phenyl)purine.Melting point: 288°-291° C.

EXAMPLE 138-(2-Methoxy-4-methanesulfonyloxy-phenyl)-1H,3H-purin-2,6-dione

This compound was prepared analogous to Example 3 in aqueous sodiumhydroxide, with the pH being maintained at between 10 and 10.5. Meltingpoint 305°-307° C. (decomp.).

The following compounds were prepared analogously:

1,3-dimethyl-8-(2-methoxy-4-methanesulfonyloxy-phenyl)-1H,3H-purin-2,6-dione,Melting point: 239°-241° C.

1,3-dimethyl-8-(2-dimethylamino-4-methanesulfonylamino-phenyl)-1H,3H-purin-2,6-dione,

8-(2-dimethylamino-4-methanesulfonylamino-phenyl)-1H,3H-purin-2,6-dione.

EXAMPLE 14 8-(2-Methoxy-4-hydroxy-phenyl)-purin-2-one

3.5 g of 2-benzyloxy-8-(2-methoxy-4-benzyloxy-phenyl)-purine (preparedby method A) was hydrogenated in 100 ml of ethanol in the presence of 1g of 20% palladium-on-charcoal at 50° C. under a pressure of 5 bar.After the catalyst had been filtered off, the filtrate was concentratedby evaporation, the residue was extracted with 2N sodium hydroxide, andthe product was precipitated by acidifying with glacial acetic acid.Further purification was effected by triturating with acetone. Yield:0.22 g (10.6% of theory). Melting point: 250° C. (decomp.).

The following point was obtained analogously:

1,3-dimethyl-8-(2-methoxy-4-hydroxy-phenyl)-1H,3H-purin-2,6-dione(hydrogenation in the presence equivalents of potassium hydroxide).Melting point: above 310° C.

Calculated: C-56.00%; H-4.66%; N-18.50%. Found: C-55.63%; H-4.67%;N-18.53%. The compounds of the present invention, that is, thoseembraced by formula I above, tautomers thereof, and non-toxic,pharmacologically acceptable acid addition salts thereof, have usefulpharmacodynamic properties. More particularly, they exhibit long-lastinghypotensive and/or positive inotropic activities in warm-blooded animalssuch as rats.

The pharmacodynamic properties of the compounds of the present inventionwere ascertained by the following method:

Determination of the effect on blood pressure and the positive inotropiceffect in anesthetized cats

The tests were carried out on cats which had been anesthetized withsodium pentobarbital (40 mg/kg i.p.). The animals breathedspontaneously. The arterial blood pressure was measured in the aortaabdominalis, using a Statham pressure transducer (P 23 Dc). To determinethe positive inotropic effect, the pressure in the left ventricle wasmeasured with a catheter-tip manometer (Millar PC-350 A). From this, thecontractility parameter dp/dt_(max) was obtained, using an analoguedifferentiator. The test compounds were injected into a vena femoralis.The solvent used was physiological saline solution of Polydiol 200. Eachcompound was tested on at least 3 cats, dosage 2 mg/kg i.v.

The following table shows the results obtained for a few representativespecies of the genus of formula I, where

A=8-(2-methoxy-4-methanesulfonyloxy-phenyl)-3(1)H-purin-2-one,

B=2-(2-methoxy-4-methanesulfonyloxy-phenyl)-5-methanesulfonyloxy-imidazo[4,5-b]pyridine,

C=2-(2-methoxy-4-methanesulfonyloxy-phenyl)-4H-imidazo[4,5-b]pyridin-5-one,

D=2-(2-methoxy-4-methanesulfonyloxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-onehydrochloride,

E=2-(2-methoxy-4-methanesulfonyloxy-phenyl)-4-methanesulfonyloxy-imidazo[4,5-c]pyridine,

F=2-(2-methoxy-4-propargyloxy-phenyl)=5H-imidazo[4,5-c]pyridin-4-one,and

G=2-(2-methoxy-4-methanesulfonyloxy-phenyl)-4H-imidazo[4,5-b]pyrazin-5-one.

    ______________________________________                                                                        Duration of                                                       Reduction in                                                                              effective action                                      Increase in Blood Pressure                                                                            (Half life)                                   Compound                                                                              dp/dt.sub.max in %                                                                        in mm Hg    in minutes                                    ______________________________________                                        A        +48        -8/-6       42                                            B        +53        -50/-42     37                                            C       +158        -54/-54     31                                            D       +117        -42/-42     31                                            E        +87        -35/-27     29                                            F       +138        -59/-47      8                                            G       +100        -26/-27      5                                            ______________________________________                                    

The new compounds are well tolerated; thus, in the test on compounds Ato G, no toxic effects on the heart or circulatory damage of any kindwas observed.

In view of their pharmacological properties, the compounds of thepresent invention are useful for the treatment of cardiac insufficiencyof various origins since they increase the contractile force of theheart and, by additionally lowering blood pressure, they facilitate theemptying of the heart.

For pharmaceutical purposes the compounds of the present invention areadministered to warm-blooded animals perorally, parenterally or rectallyas active ingredients in customary pharmaceutical compositions, that is,compositions consisting essentially of an inert pharmaceutical carrierand an effective amount of the active ingredient, such as tablets,coated pills, capsules, wafers, powders, solutions, suspensions,emulsions, syrups, suppositories and the like. An effective amount ofthe compounds of the present invention is from 0.1 to 5 mgm/kg bodyweight, preferably 0.5 to 2.0 mgm/kg body weight, 1 to 4 times daily.

The following examples illustrate a few pharmaceutical compositionscomprising a compound of the present invention as an active ingredientand represent the best modes contemplated of using the invention. Theparts are parts by weight unless otherwise specified.

EXAMPLE 15 Tablets

The tablet composition is compounded from the following ingredients:

    ______________________________________                                        2-(2-Methoxy-4-methanesulfonyloxy-phenyl)-                                                              100.0  parts                                        5H--imidazo[4,5-c]pyridin-4-one hydro-                                        chloride                                                                      Lactose                   50.0   parts                                        Polyvinylpyrrolidone      5.0    parts                                        Carboxymethylcellulose    19.0   parts                                        Magnesium stearate        1.0    parts                                                                  175.0                                               ______________________________________                                    

Preparation:

Moist screening: 1.5 mm Drying: Circulating air dryer, 50° C Dryscreening: 1 mm

Add the remaining excipients to the granulate and compress the finalmixture into 175 mg-tablets. Each tablet contains 100 mg of the activeingredient.

Example 16 Coated tablets

The tablet core composition is compounded from the followingingredients:

    ______________________________________                                        2-(2-methoxy-4-methanesulfonyloxy-phenyl)-                                                              50.0   parts                                        5H--imidazo[4,5-c]pyridin-4-one hydro-                                        chloride                                                                      Dried corn starch         20.0   parts                                        Soluble starch            2.0    parts                                        Carboxymethylcellulose    7.0    parts                                        Magnesium stearate        1.0    parts                                                                  80.0   parts                                        ______________________________________                                    

Preparation:

Moisten the active ingredient and starch evenly with an aqueous solutionof the soluble starch.

Moist screening: 1.0 mm Dry screening: 1.0 mm Drying: 50° C. in acirculating air dryer.

Mix the granulate and remaining excipients and compress into 80mg-tablet cores.

The finished cores are provided with a sugar coating in the usual way ina coating vessel. Weight of coated tablet: 120 mg, each containing 50 mgof the active ingredient.

EXAMPLE 17 Suppositories

The suppository composition is compounded from the followingingredients:

    ______________________________________                                        2-(2-Methoxy-4-methanesulfonyloxy-phenyl)-                                                            75.0     parts                                        5H--imidazo[4,5-c]pyridin-4-one-                                              hydrochloride                                                                 Suppository base (e.g. cocoa butter)                                                                  1625.0   parts                                                                1700.0   parts                                        ______________________________________                                    

Method of preparation:

The suppository base is melted. At 38° C. the ground active ingredientis homogeneously dispersed in the melt. It is cooled to 35° C. andpoured into chilled suppository molds. Weight of suppository: 1.7 gcontaining 75 mg of the active ingredient.

EXAMPLE 18 Hypodermic solution

The solution is compounded from the following ingredients:

    ______________________________________                                        2-(2-Methoxy-4-methanesulfonyloxy-phenyl)-                                                            50.0    parts                                         5H--imidazo[4,5-c]pyridin-4-one hydro-                                        chloride                                                                      Sorbitol                250.0   parts                                         Distilled water q.s.ad  5000.0  parts                                                                         by vol.                                       ______________________________________                                    

Preparation:

The active ingredient and sorbitol are dissolved in distilled water, thesolution is diluted to the stated volume and filtered under sterileconditions.

Packaging: in 5 ml ampules, each containing 50 mg of the activeingredient.

Sterilizing: 20 minutes at 120° C.

EXAMPLE 19 Drop solution

The solution is compounded from the following ingredients:

    ______________________________________                                        2-(2-Methoxy-4-methanesulfonyloxy-phenyl)-                                                           5.0    parts                                           5H--imidazo[4,5-c]pyridin-4-one hydro-                                        chloride                                                                      Methyl p-hydroxybenzoate                                                                             0.035  parts                                           Propyl p-hydroxybenzoate                                                                             0.015  parts                                           Anisole                0.05   parts                                           Menthol                0.06   parts                                           Sodium saccharin       1.0    parts                                           Glycerol               10.0   parts                                           Ethanol                40.0   parts                                           Distilled water q.s.ad 100.0  parts by vol.                                   ______________________________________                                    

Preparation:

The benzoates are dissolved in ethanol, and then the anisole and mentholare added. The active ingredient, glycerol and sodium saccharindissolved in water are then added. The solution is then filtered untilclear.

Any one of the other compounds embraced by formula I, a tautomer thereofor a non-toxic, pharmacologically acceptable acid addition salt thereofmay be substituted for the particular active ingredient in Examples 15through 19. Likewise, the amount of active ingredient in theseillustrative examples may be varied to achieve the dosage unit range setforth above, and the amounts and nature of the inert pharmaceuticalcarrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:
 1. A compound of the formula ##STR12## wherein, among the fourring members A, B, C or D, one is --N═, two are --CH═, and one is##STR13## R₁ is NC--CH₂ --O--, HOOC--CH₂ --O--, R₃ --OOC--CH₂ --O--, R₃SO₂ --O--, R₃ SO₂ --NH--, R₃ SO₂ --NR₃ -- or R₄ --O--;R₂ is R₃ O--,##STR14## R₅ --O--; R₃ is alkyl of 1 or 4 carbon atoms; R₄ is alkynyl of2 of 5 carbon atoms; and R₅ is alkenyl of 2 of 5 carbon atoms or alkynylof 2 to 5 carbon atoms;a tautomer thereof; or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 2. A compoundof claim 1, whereA, B, C, D, R₁ and R₂ have the meanings defined inclaim 1; R₃ is methyl; R₄ is propargyl; and R₅ is allyl or propargyl;atautomer therof; or a non-toxic, pharmacologically acceptable acidaddition salt thereof.
 3. An imidazo[4,5-b]pyridin-5-one,imidazo[4,5-c]-pyridin-4-one or imidazo[4,5-c]pyridin-6-one of claim 1,whereR₁ is propargyloxy, methanesulfonyloxy, methanesulfonylamino orN-methyl-methanesulfonylamino; and R₂ is methoxy or dimethylamino;atautomer thereof; or a non-toxic, pharmacologically acceptable acidaddition salt thereof.
 4. A compound of claim 3, whereR₂ has themeanings defined in claim 1; and R₁ is methanesulfonyloxy,methanesulfonylamino or N-methyl-methanesulfonylamino;a tautomerthereof; or a non-toxic, pharmacologically acceptable acid addition saltthereof.
 5. A compound of claim 1, which is2-(2-methoxy-4-methanesulfonyloxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one,a tautomer thereof; or a non-toxic, pharmacologically acceptable acidaddition salt thereof.
 6. A compound of claim 1, which is2-(2-methoxy-4-methanesulfonyloxy-phenyl)-5-methanesulfonyloxy-imidazo[4,5-b]pyridine,a tautomer thereof; or a non-toxic, pharmacologically acceptable acidaddition salt thereof.
 7. A compound of claim 1, which is2-(2-methoxy-4-methanesulfonyloxy-phenyl)-4H-imidazo[4,5-b]pyridin-5-one,a tautomer thereof; or a non-toxic, pharmacologically acceptable acidaddition salt thereof.
 8. A compound of claim 1, which is2-(2-methoxy-4-methanesulfonyloxy-phenyl)-4-methanesulfonyloxy-imidazo[4,5-c]pyridine,a tautomer thereof; or a non-toxic, pharmacologically acceptable acidaddition salt thereof.
 9. A compound of claim 1, which is2-(2-methoxy-4-propargyloxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one, atautomer thereof; or a non-toxic, pharmacologically acceptable acidaddition salt thereof.
 10. A hypotensive or cardiotonic pharmaceuticalcomposition consisting essentially of an inert pharmaceutical carrierand an effective hypotensive or cardiotonic amount of a compound ofclaim
 1. 11. The method of lowering the blood pressure or increasing thecontractility of the heart muscle in a warm-blooded animal in needthereof, which comprises perorally, parenterally or rectallyadministering to said animal an effective hypotensive or positiveinotropic amount of a compound of claim 1.